ABSTRACT Down Syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Persons with Ds demonstrate cognitive deficits in addition to co- morbidities including cardiovascular alterations and pulmonary hypertension. Lower blood pressure at rest and in response to exercise and other stressors are prevalent in Ds. The attenuated cardiovascular reactions to activities of daily living in Ds are autonomically mediated, but likely include other factors such as endothelial dysfunction. These cardiovascular findings are complicated by the fact that Ds is protected from atherosclerosis. Therefore, the mechanisms responsible for cardiovascular alterations in Ds are multifaceted in this population. At this time there is not an appropriately developed cardiovascular model to investigate these important clinical concerns, although a trisomic animal model does exist. Our robust preliminary data reveal attenuated mean arterial blood pressure, diastolic blood pressure and systolic blood pressure in restrained Ts65Dn mice, a model of Ds. Freely moving Ts65Dn mice have lower heart rate than wild-type (WT). Taken together, these data suggest the altered cardiovascular patterns observed in Ts65Dn mice may be representative of people with Ds. This exploratory grant application aims to verify, via a series of physiological experiments, that the Ts65Dn mouse is an appropriate model to study heart and blood pressure differences in Ds. The experiments described in this proposal will further examine cardiovascular alterations in Ts65Dn mice through conscious and reduced preparations, including autonomic nervous system contributions and endothelial dysregulation as a potential mechanism of attenuated vascular tone and cardiac output. Specific Aim 1 will compare the cardiovascular profile and vascular physiology of WT and Ts65Dn mice at 3, 6 and 12 months of age. Blood pressure and heart rate will be quantified across the circadian cycle via radiotelemetry, and we will further distinguish possible mechanistic differences in autonomic control of blood pressure with pharmacological blockade of the sympathetic and parasympathetic nervous system in conscious mice. Arterial stiffness will be quantified in anesthetized mice using pulse wave velocity, and heart rate variability will be used to monitor autonomic tone in both conscious and anesthetized experiments. Arterial isometric tension using an in vitro setup will compare endothelial dependent and independent vasodilation of aorta and mesenteric artery. Specific Aim 2 will quantify baroreflex sensitivity and cardiac function with in vivo pressure-volume loops in WT and Ts65Dn mice. All aims will study male and female mice at 3 months, 6 months and 12 months of age to further describe aging and sex as biological variables in this model. Since individuals with Ds demonstrate characteristics of accelerated aging it will be important to know how heart function and blood pressure responses change with advancing age in WT vs. Ts65Dn. Overall, this project will provide insight into cardiovascular regulation in Ds with the objective of improving the quality of life of persons with this condition. !